1. Field of the Invention
This invention relates generally to a new and improved system for sampling and analysis of body fluids and the like, and may also include delivery of therapeutic agents in response to such analysis. More particularly, the invention relates to new and improved methods and apparatus for non-invasively withdrawing analytes from a biological subject automatically and controlling subsequent administration of therapeutic agents.
2. Description of the Related Art
Diagnosis for many human ills is dependent on evaluation of invasive samples of body fluids taken for assay. This invasive procedure is accomplished by withdrawal of the analyte or sample through a needle or the like, with consequent exposure of the patient to injury, possible infection and discomfort. The procedure invariably involves medical professionals that add to the cost of the procedure, e.g. an office visit.
Advances have recently been made in the biosensor field that enable diabetics, for instance, to self-test through the convenience of kits such as the ExacTech(copyright) device disclosed in U.S. Pat. Nos. 4,545,382 and 4,711,245. Such a device, while performing a valuable service and representing a quantum leap over professional intervention, is however, still invasive and subjects the patient to the same risks through multiple pin pricks and the like.
One approach to overcoming the aforementioned major shortcomings of invasive procedures is by noninvasive electro-osmotic analyte withdrawal through the unbroken skin or mucosal membrane. Electro-osmosis, sometimes referred to as cataphoresis and/or reverse iontophoresis, was recognized before 1941 by Nernst who showed that urea and sugar can be electrically transported out of the unbroken skin. An extensive bibliography exists on this basic phenomena.
A recent effort by Guy, et al., e.g. as described in U.S. Pat. Nos. 5,279,543 and 5,362,307, attempts to use this basic electro-osmosis technology to extract glucose. However, these attempts fall short of practical success because the proposed technology cannot perform the desired withdrawal procedure within a time span of less than ten minutes, as medically needed so that a glucose measurement would be followed in a timely manner after determination of the appropriate therapeutic insulin level. In this regard, continuously rapid changes of glucose levels, which commonly occurs, require different therapeutic insulin levels. Such limiting constraints on faster performance of sample withdrawal by the prior art is due to the restricted levels of current, voltage and time duration for the device to extract a sample and yet prevent skin injury. Accordingly, the prior art systems offer nothing new in basic electro-osmosis technology to prevent skin injury. Moreover, there is no subsequent controlled automatic delivery of an appropriate therapeutic agent in response to such rapid sample withdrawal and analysis.
Further difficulties have been encountered in achieving satisfactory dosimetry control for iontophoretic administration systems.
Hence, those concerned with the development and use of analyte withdrawal and evaluation systems have long recognized the need for very rapid, painless, accurate, non-invasive analyte withdrawal and analysis and subsequent controlled automatic delivery of therapeutic agents in response to such analysis. The present invention clearly fulfills all these needs.
Briefly, and in general terms, the present invention provides a new and improved system for sampling and analysis of body fluids, e.g., analytes, and delivery of therapeutic agents in response to such analysis and, more particularly, to improvements in methods and apparatus for non-invasively withdrawing and accurately evaluating analytes quickly, painlessly and reliably from a biological subject automatically and controlling subsequent administration of therapeutic agents in response to such analyte sample analysis.
By way of example, and not necessarily by way of limitation, the present invention provides a system wherein limits of low electrical voltage and current previously imposed on prior art systems to prevent skin injury, are now overcome through unique electrical circuitry and long tunnel physical routing of applied electrical voltage, thereby achieving high sampling current density. This facilitates rapid sampling which can be completed well under 10 minutes. In this regard, the process of the present invention enables use of 60 volts or more producing a controlled sampling current for complete comfort, and provides an analyte reading in 15 seconds or less.
In accordance with the invention, the aforedescribed features are accomplished, in part, by providing a long tortuous path between the applied high voltage and the skin of a biological subject. This path between the voltage source and the skin typically consists of a solvent or water wetted wool as an intervenor. Since the injury is caused by sodium hydroxide (lye) migrating from the negative voltage source electrode, the wool (or composite) acts as a barrier to the rather large sodium hydroxide molecule to prevent injury within the 10 minute treatment period.
Since one aspect of the invention involves a diagnostic tool, accuracy and repeatability are paramount. To achieve this, the invention provides that the current and time used to obtain the analyte sample be integrated and interdependent on each other, so that the identical quantitative sampling is always obtained. In this way, the identical amount of analyte is always withdrawn as a sample, despite the substantial variabilities of skin resistance on an individual.
Another aspect that limits the use of higher electrical currents is the pain involved. Usually, both electrical polarities are in direct contact with the skin through a felt or gel intervenor. Of the two polarities, the sensation at the positive electrode is typically far more painful. If therefore, direct contact of the positive electrode is removed from the skin, it allows a large increase in sampling current without the discomfort normally associated with such electrical currents and while still obtaining the analyte such as glucose at the negative electrode.
To eliminate pain caused by the positive polarity at high currents, additional novel technology is provided in accordance with the invention. Previously used circuitry in iontophoresis used both electrical polarities applied to the skin surface to xe2x80x9ccompletexe2x80x9d or ground the circuit. In the practice of the present invention, the negative polarity is chosen to sample an analyte such as glucose and the positive electrode is no longer directly connected to the body as a ground return but stays within the device housing with its dropping resistor connected to the skin (ground) to complete the circuit. This ground is essentially neutral electrically. The negative polarity is in electrical contact with the skin through the aforedescribed wetted, long wool intervenor and then through a wetted membrane on the skin which acts as a collector for the analyte. Of course, for other applications these polarities could be reversed and, again, only a single electrical polarity is in contact with the skin.
The present invention also provides a system to assay or measure the sample. A pair of electrodes are provided facing each other with analyte selective enzyme coated on one electrode, e.g., the working electrode, or, alternatively, on the membrane facing the working electrode. A bi-layer membrane is inserted between these electrodes and serves the purpose of connecting directly to the skin on one end while the other end is in contact with the long narrow intervenor that is connected to the high voltage negative source. When wetted with an electrolyte of pH 7.4, a continuous circuit is provided from this high voltage source to the skin (with felt pad and membrane in between). Thus, in accordance with the invention, a xe2x80x9csandwichedxe2x80x9d bi-layer membrane in between an enzyme coated electrode(s) or membrane is provided as a mechanical structure to extract the analyte sample and convey it to any appropriate digital readout subsystem.
The biosensor circuit is separate from the withdrawal circuit and comes into play after the analyte sample has been withdrawn. The dosimetry circuit turns the device on for the predetermined setting of less than 15 ma./sec., for example, to extract the analyte. Upon completion of this cycle, the readout subsystem is activated and provides a reading on its digital display. Of course, any number of detection systems are available and would be suitable for the readout subsystem, including those in the public domain.
In accordance with the invention, electronically produced gases serving as a mediator are generated at the high voltage negative terminal. The negative polarity, besides producing the necessary current to withdraw the analyte, also produces hydrogen gas at the negative pole which migrates towards the positive pole and thus passes through the membrane and between the biosensor electrodes. The hydrogen gas is a reduction agent and reduction cannot exist without oxidation. This oxidizes the immobilized enzymes on the electrodes/membrane and the captured glucose analyte. This also causes electron transfer to the electrodes that is proportionate to the concentration of analyte.
Hydrogen gas is an excellent redox species and is far superior to the xe2x80x9cone shotxe2x80x9d mediator of prior art devices, such as that utilized in the well-known and commercially available ExacTech(copyright) system, because it comes from a renewable source. This process also produces the halogen chlorine which further aids in oxidation.
In addition, in accordance with the invention, the high voltage source is dosimetry controlled and, therefore, not only quantitatively controls the analyte withdrawal, but also controls the quantity of the aforementioned hydrogen/chlorine gas mediator which is generated.
This negative electrode generated hydrogen also serves other important functions. Since hydrogen has a special affinity for palladium and will permeate its surface, this may be used to advantage by providing a sensor electrode of palladium. Hydrogen interacts with the palladium to lower resistance. If the working electrode is palladium and the second electrode is of the hydrogen resistive alloy NASA-23 or its equivalent, the resistance or work function between both electrodes is lowered. Because the NASA-23 or equivalent electrode is impervious to the hydrogen gas, it serves as an excellent reference electrode relative to the palladium electrode.
Still other benefits accrue when hydrogen ions combine with the solvent water molecules to create hydronium ions. The hydronium ions are crucial to the cellular processes which lead to enzyme catalysis and membrane transport.
In accordance with the invention, very high potentials (over 1v.) are provided to cause the redox reaction. There is a two-step process, i.e., 1) a high voltage to cause the redox (generated by the reducing agent hydrogen), and 2) then revert to an extremely small voltage (under 1v.) to activate the transducer and readout system. This occurs almost instantaneously because the conventional time of 20-30 seconds to await the redox reaction has already taken place in much less time by the high voltage caused hydrogen that led to that event in shorter time than any prior art device.
Accordingly, and in view of the foregoing, the process of the present invention includes application of a large negative voltage to a small area of the skin to cause the electro-osmotic withdrawal of body fluids. This same high voltage has another attribute in that it generates hydrogenxe2x80x94the same hydrogen gas that will lead to the oxidation of the glucose enzyme(s) that separates out the glucose analyte from interferents. This causes the cycle of events that will result in electron transfer from the closely associated enzyme(s) coated electrodes or membranes to provide a measure of glucose concentration. Moreover, the source for the hydrogen is unlimited and repeatable, therefore making the process available on demand without the physical presence of any consumable chemical mediators. Since the enzymes are reusable, the economy and simplicity of operation of such a device provides clear advantages to the patient.
To reuse the device and obtain new glucose measurements and repeat the events leading to insulin infusion, known as recovery time, the second half of the one cycle long signal may (optionally) reverse polarity and return the system to neutral. Alternatively, one just has to wait several minutes for the hydrogen to dissipate, and the entire process can then be repeated.
Another feature of the present invention that improves the minute sampling taken through the unbroken skin is the use of the amplification or regeneration capability of certain chemical combinations. If the electrodes are coated with coupled enzymes, such as glucose oxidase or glucose dehydrogenase in the presence of cofactors NAD/NADH and HADPH or NADH, then the extremely minute analyte coming through the skin is xe2x80x9cping pongedxe2x80x9d between competitive enzymes and, therefore, multiplied. Another benefit of this is improved separation between the target glucose and interferents.
Hence, various aspects of the present invention facilitate noninvasively withdrawing body fluid and provide novel sensor technology to create a mediator and to control the quantity of this mediator for accurately determining analyte concentration for diagnostic purposes. These inventive features can be used separately or in combination and they both use common components that have multiple functions. This dual capability of noninvasive sampling and controlling the target inorganic or organic substance is a linchpin to the control and operation of a therapeutic drug delivery unit such as that described in U.S. Pat. No. 5,224,927 by the same inventor, Robert Tapper, as the present invention. This xe2x80x9cclosed loopxe2x80x9d arrangement provides for self-regulated insulin infusion controlled by the monitored glucose reading using the biosensor described above. The entire device can fit into an externally worn, topically applied xe2x80x9cpatchxe2x80x9d.
Another important feature referred to in U.S. Pat. No. 5,224,927 is the ability of this device to adjust the pH of the drug delivery reservoirs and/or a biosensor skin contact membrane (known as BLM or s-BLM). The pH adjustment range is approximately 4 to 8 and can aid in permeability for both infusion of drug or increasing withdrawal of analyte. For instance, in view of the nonconductive wetted collection bi-layer membrane (BLM) in contact with the skin, and in view of the poorly conductive insulin in the drug delivery chambers, optimal performance would take place if the solution were adjusted to the appropriate pH. An important function of the s-BLM membrane is that it can be used as a pH probe for pH measurement. The resulting pH data is then the basis for any suitable pH control circuit to adjust pH as needed.
The aforedescribed system of the present invention relates in particular, and only by way of example, to the needs of a diabetic. Another need of the diabetic is that they be given a xe2x80x9cbolusxe2x80x9d shot of insulin at mealtime. A bolus shot requires the infusion of a large dose of insulin compared to the patient""s baseline maintenance level of insulin. The system described in U.S. Pat. No. 5,224,927 is readily adapted to meet this demand for an extra large dose in the following manner.
By activating a designated electrical bolus switch, both drug delivery reservoirs of the patch are made active simultaneously instead of their normal operating mode of sequential drug delivery (due to the very slow A.C. operating signal). Since the bolus switch causes both reservoirs to deliver insulin simultaneously by giving them the identical negative polarity, the dosage is thereby doubled over baseline.
As previously indicated, the positive polarity stays within the electronic patch housing and is connected to the skin through a dropping resistor. The skin or ground is relatively neutral at this point. This feature lifts the positive polarity off the skin, thereby eliminating the more painful and non-contributing polarity from skin contact. This, in turn, allows the patient to at least double the electrical current setting, thereby again doubling dosage for a total of four times over maintenance level for short term delivery. For this short term delivery a D.C. signal is used. Because it is a D.C. signal, skin injury could be expected unless corrective action were taken. Until now, the use of the pH control circuit served the singular purpose of optimizing permeability and, therefore, delivery by making the solvent compatible with the drug of choice and its polarity.
In accordance with the invention, pH control is also used to prevent skin injury when using D.C. for the short term. For instance, in the example cited above, the negative polarity was used to drive insulin from both reservoirs. The injurious sodium hydroxide generated at the negative pole must then be offset. This can be done by pretreating with the positive polarity, thereby building an acidic reserve pH of approximately 4 (by way of example) in the drug delivery reservoirs. Drug delivery is then activated with a negative polarity driving the pretreatment pH up toward the alkaline state. Before the reservoirs reach pH 8, the delivery signal must be stopped for another short dosage of pH 4 caused by the positive polarity. Thus, in the practice of the present invention, injury is prevented by avoiding extremes of pH as measured by the s-BLM probe.
The present invention also includes a unique electrode system that allows current to be elevated at least 200% over present levels. A pair of large drug delivery electrodes is provided. In accordance with the invention, another pair of ancillary electrodes are added on the outside perimeter of the drug delivery electrodes. These ancillary electrodes also cross between and are insulated from the drug delivery electrodes. The outer ancillary electrodes are also typically driven at a frequency of approximately one cycle per minute. This is the second harmonic of the basic drug delivery generator whose frequency is approximately one cycle every two minutes. It has also been discovered that the use of sodium salicylate instead of tap water with these ancillary electrodes is able to further mask the pain sensation arising from the drug delivery electrodes, so as to facilitate additional large increases in the drug delivery electrical current levels.
Another important need for a bolus shot is in the field of anesthesia since it is desirable for quick action to alleviate pain. The same procedure for elevated infusion applies as described above with pH control to avoid injury, but may require switching polarities since many analgesics are positive. In this regard, and by way of example, a D.C. signal is used with novel circuitry to obtain greatly elevated drug delivery levels without skin injury or pain. To lessen pain and skin injury from the positive reservoirs, these electrodes are connected through a dropping resistor, instead of connecting them directly to the positive terminal of the voltage supply. This causes a large drop across the resistor and makes the electrode relatively less positive than the source voltage. Electrical current still flows because the negative polarity is directly connected to the skin through the wetted pad. This provides a lifting and isolation of the pain-causing high positive voltage relative to the skin, and also allows increased electrical current and therefore faster therapy. Diminished positive voltage at the skin also decreases the potential for irritation from this contact. Importantly, it has been discovered that adding sodium salicylate to the negative pad also diminishes skin injury which would be a concern with a D.C. device.
The aforedescribed artificial pancreas of the present invention has obvious advantages over present day invasive systems that include expensive and risky implants.
It is to be understood that the noninvasive biosensor described above used glucose as the target analyte only as an example and not by way of limitation. For instance, there are hundreds of different dehydrogenases and several thousand enzymes. Besides glucose analysis, important diagnostic applications could include, again by way of example only, urea, creatinine, lactate, cholesterol, aspirin and paracetamol, among others. In addition, noninvasive sample analysis may be made of body fluids to compare then to normal levels or to track administered drug levels.
Since the present invention focuses on a means of determining the concentration of chemical or body fluid components to assess a condition, another important application is facilitated. During iontophoretic drug delivery, it has long been an enigma to determine what portion of the reservoir drug has been infused. In this regard, the same means of determining concentration with the biosensor described above may be applied to assessing the drug remnant in a drug infusing device, therefore assuring the user of adequate drug availability, etc. This occurs because a decrease of concentration indicates percutaneous absorption into the body of the solute or drug. This information may also be important to the investigator during the testing of a new drug, for quantitative analysis of drug related to an effect. The present invention thus nominally replicates the extremely expensive HPLC lab instrument at a fraction of the cost.
Still another important application in accordance with the invention, comes about as a result of this ability to assess drug concentration in an iontophoretic drug delivery reservoir. It has always been a problem to have an adequate supply of drug available in the drug reservoir for long term, continuous delivery. It is not practical to make an overly large patch because it must be worn and would meet patient objection. Moreover, the literature places concentration restrictions on iontophoretic drug delivery to 2% solutions, claiming reduced flow above this point because of ionic clutter. In accordance with the present invention, a novel way of eliminating this problem and allowing delivery over time with a relatively small patch is to provide a reserve reservoir that contains a concentrate of the desired drug in aqueous solution. This concentrate is considerably over 2%xe2x80x94perhaps 20 or 50%. Upon receiving information from the drug delivery reservoir that the concentration is less than the initial filling of 2%, the biosensor triggers the reserve reservoir to release enough of the concentrate to make up the difference that was infused. In this manner, the drug delivery reservoir is continuously replenished.
The structure of the reserve reservoir is a separate compartment for the concentrate with a membrane covered opening. The membrane has a voltage across it with selective polarities to act as a valve to open or shut off the flow of concentrate as needed. This action may be enhanced with an ion exchange membrane. The solvent is replenished automatically by virtue of the fact that an A.C. signal is used. This causes the hydrogen and hydroxide ions to migrate together to form water.
Various other embellishments known in the art can be practiced in this invention. They include immobilization of the enzyme biocomponent and restriction of the flow of analyte diffusion. The best biosensor design is to build a xe2x80x9cdirectxe2x80x9d device with biocomponents immobilized directly on the transducer. Other characteristics of construction include the close proximity of the biological and physicochemical components to each other to improve efficiency.
The present invention also provides in combination with the aforedescribed sample withdrawal and assay, and in response to electrical input from the assay subsystem, a new and improved method and apparatus for applying electrical energy topically to a suitable surface of a biological subject, such as the skin of a human body, particularly for the long term administration of medicaments and the like or for other electrotherapeutic treatment, and by which the aforementioned deficiencies and undesired side effects are greatly minimized and may be eliminated.
Moreover, the system of the present invention is relatively inexpensive to manufacture, can be physically packaged in a completely self-contained, relatively simple and compact configuration, is trouble free and reliable in use, is capable of higher drug administration rates and drug concentrations, can deliver multiple drugs simultaneously in a simple manner, can control pH at the delivery site, is capable of delivering large and/or heavy molecule drugs, is a more effective bactericidal, and is arranged to be safely, simply and reliably operated for self-treatment by an average person in normal home use, even for extended periods of several days at a time to unlimited use for the chronically ill patient. Furthermore, it is contemplated in the practice of the invention that electrical impedance at the administration site on the patient can be substantially reduced to vastly improve permeability and penetration and thereby further enhance medicament delivery.
In this regard, the present invention is directed to the combination of a new and improved system for iontophoretic drug administration, in response to an assay measurement signal, which includes conducting direct electrical current through the skin of a body, and periodically reversing the electrical current and conducting the current through the skin in the opposite direction, to effectively deliver very low frequency A.C. current, substantially in the critical range of approximately 0.0027 Hz to 10 Hz. It has been discovered (see U.S. Pat. No. 5,224,927) that, within this substantially critical frequency window between approximately six minutes per full cycle and approximately ten cycles per second, a dramatic cancellation of skin damaging ions takes place. At frequencies higher than approximately 10 Hz, no substantial effective delivery takes place. At frequencies lower than approximately 0.0027 Hz, the risk of skin injury increases substantially.
As previously indicated, it is well known that the positive iontophoretic electrode, in addition to its primary function of driving like polarity ionic substances into the skin of a subject, unfortunately produces skin damaging hydrochloric acid as well. Likewise, the negative iontophoretic electrode, in addition to its primary function of driving like polarity ionic substances into the skin, unfortunately also produces skin damaging sodium hydroxide. However, within the aforestated frequency range of the present invention, either driving polarity delivers the desired ionic therapeutic substances, but also cancels the undesired skin damaging ions with the reverse portion of the electrical cycle. The reason for neutralization of the harsh injury producing chemicals, i.e., hydrochloric acid and sodium hydroxide, is that both of these chemicals require a finite period of time on the skin to cause damage. Hence, these damaging chemicals are made to cancel each other before damage takes place, by critical frequency selection, in accordance with the invention, of the A.C. driving signal. Therefore, optimization of a long sought therapeutic device with reduced side effects has been achieved.
In this regard, electronic circuitry is provided to automatically impose the reversal of electrical current at regularly repeating intervals of time, in accordance with the aforedescribed substantially critical frequency range, and the system can be adjusted to conduct the iontophoretic treatment at any desired level of electrical current, such treatment being under the control of the previously described sample withdrawal and assay subsystem.
The present invention also provides, as previously indicated, a method and apparatus for electrical dosimetry control in the application of electric currents to withdrawal of analyte samples, dosimetry in sample withdrawal being determined automatically by the product of time and administered electrical current. In this regard, the present invention is directed to a system for electrical dosimetry measurement and control, wherein the product of administered electrical current and time for total dosage is maintained constant, while either variable, time or electrical current magnitude, may be changing.
By way of example and not necessarily by way of limitation, the system includes means for automatically establishing the magnitude of the desired total sample withdrawal dosage in terms of delivered time-current product and means for sensing the magnitude of the electrical current and converting that magnitude to a voltage for varying the frequency of a voltage controlled oscillator as a function of the electrical current magnitude. Means are also provided for measuring and accumulating the electrical output of the oscillator over time, in a suitable counting device, as an indication of the actually delivered time-current product. In addition, means are provided for comparing the delivered time-current product registered in the counter, as a running measure of withdrawn sample dosimetry during the sampling procedure, with the desired total dosage previously established, so that the application of the sample withdrawing electrical current will be terminated when the time-current product actually administered equals the desired total withdrawal dosage.
The new and improved electrical dosimetry control system of the present invention for sample withdrawal is extremely accurate, reliable and easy to use. The system provides enhanced patient comfort and high precision in automatically establishing administered electrical current dosage for consistent sample withdrawal.
Hence, the present invention provides a new and improved method and apparatus for very rapid, painless accurate, non-invasive analyte withdrawal and analysis and subsequent controlled automatic delivery of therapeutic agents in response to such analysis. The invention also provides new and improved subsystems and components for enhancing the practice of the invention.
These and other objects and advantages of the invention will become apparent from the following more detailed description, when taken in conjunction with the accompanying drawings of illustrative embodiments.